1. Field of the Invention
The present invention relates generally to the field of treatment of autoimmune disease, such as multiple sclerosis (MS). More particularly, it concerns a T-cell receptor sequence found in some MS patients, and methods for its detection.
2. Description of Related Art
In humans and other mammals, T cell receptors are found on T cells. T cell receptors comprise .alpha. and .beta. chains, with .beta. chains comprising the following regions from N-terminus to C-terminus: V.beta.-D.beta.-J.beta.-C.beta.. T cell receptors naturally vary in the V.beta.-D.beta.-J.beta. regions.
When an antigen is presented to the T cells by an antigen-presenting cell (APC), a T cell receptor with variable regions (including V.beta.-D.beta.-J.beta.) that so happen to recognize the antigen binds to the antigen on the APC. The T cell bearing the T cell receptor then undergoes activation (clonal expansion).
The pathogenesis of a number of autoimmune diseases is believed to lie in autoimmune T cell responses to antigens presented normally by the organism. An example of such a disease is multiple sclerosis (MS), which is generally held to arise in T cell responses to myelin antigens, in particular myelin basic protein (MBP). MBP-reactive T cells are found to undergo in vivo activation, and occur at a higher precursor frequency in blood and cerebrospinal fluid in patients with MS as opposed to control individuals. These MBP-reactive T cells produce Th1 cytokines, e.g. IL-2, TNF, and .gamma.-interferon. These Th1 cytokines facilitate migration of inflammatory cells into the central nervous system and exacerbate myelin-destructive inflammatory responses in MS.
A number of regulatory mechanisms can be made use of in the treatment of MS. One such is vaccination with one or more of the limited number of T cell membrane-associated peptides with extracellular domains. Vandenbark, U.S. Pat. No. 5,614,192, discloses treatment of autoimmune diseases by the use of immunogenic T cell receptor peptides of 15 to 30 amino acids comprising at least part of the second complementarity determining region (CDR2) of the T cell receptor. A copending U.S. patent application by Zhang (No. 60/099,102) discloses treatment of autoimmune diseases by use of immunogenic T cell receptor peptides in combination with immunogenic T cell activation marker peptides.
One area in which vaccination with T cell receptor peptides can be improved is by determining which, if any, common motifs are found in the T cell receptors of a patient with an autoimmune disease such as MS. If such motifs are found, then the patient can be vaccinated with peptides identical to the motifs, in order to facilitate treatment.
Therefore, it is desirable to have the amino acid sequences of common motifs found in the T cell receptors of patients with autoimmune diseases. It is also desirable to be able to readily detect such motifs in a patient sample by a convenient method, such as PCR. In addition, it is desirable to use peptides identical to the detected motifs to treat a patient with the autoimmune disease.
The present invention discloses such a common motif found in the T cell receptors of a subset of V.beta.13.1 T cells, the "LGRAGLTY motif", which has the amino acid sequence Lue Gly Arg Ala Gly Leu Thr Tyr (SEQ ID NO: 3), as well as a method for its ready detection by PCR. This motif is found in some T cell receptors of some T cells that recognize amino acids 83-99 of MBP (hereinafter "MBP83-99"). The motif in the context of this subset of V.beta.13.1 T cells may hereinafter be referred to as "V.beta.13.1-LGRAGLTY." Peptides identical to the motif can be used to vaccinate patients in order to treat or prevent autoimmune diseases with which V.beta.13.1-LGRAGLTY is associated. One such autoimmune disease is MS.